Hip fractures are the most devastating result of osteoporosis, and for most patients, the first step in downward spiral of lost ambulation, lost independence, institutionalization, and secondary medical morbidity and mortality. Within one year of hip fracture, 50% of patients will be unable to walk without assistance, 25% will require long-term care, and 20% will have died One potent regulator is physical loading (Krahl et al. 1994), however the cellular sensing mechanism has proven to be elusive. Our laboratory is among one of the first demonstrating that the recently described osteocyte primary cilium appears to play a major role in this process (Malone et al. 2007). Primary cilia are single solitar cellular extensions, possessed by virtually every in the body, but whose function remains elusive. As osteocyte mechanosensors, these organelles acting synergistically with other previously identified mechanisms to regulate bone metabolism. Our contribution here is expected to be elucidating the role that primary cilia microdomains play in osteocyte mechanotransduction and to identify the intracellular signaling mechanism involved. This contribution is significant because it is a critical initial step that will catalyze a continuum of research expected to lead to novel pharmacologic therapeutic strategies that mimic mechanical loading at a molecular level. The long-term goal of this project is to determine how primary cilia contribute to bone's ability to sense and respond to mechanical loading. The overall objective of this application is to identify their precise functional role. We will achieve this objective determining the mechanically activated osteocyte intraciliary and intracellular signaling pathways (SA1), whether osteocyte primary cilia regulate osteoblastic osteogenesis (SA2), and establish the role of osteocyte primary cilia transduction in mechanically induced bone formation (SA3). At the conclusion of the project we hope to have demonstrated that primary cilia act as osteocyte mechanosensors, elucidated the molecular sensor and signaling pathway involved, and demonstrated, at least in principle, in vivo and in vitro. Prevention of osteoporosis will resut in a dramatic increase in quality of life, reduce morbidity, and reduce health care costs. A collateral benefit will be contributing to the emerging picture of primary cilia as a nexus of extracellular signal sensing and integration in bone and other cell types. PUBLIC HEALTH RELEVANCE: Osteoporosis is a devastating disease that causes significant social costs and human suffering. Primary cilia are solitary cellular antennae that have recently been shown to sense a variety of extracellular signals in bone and other tissues, including mechanical stimulation. In this project we will establish the role of primary cilia as cellular mechanosensors in bone and the molecular mechanism involved with the aim of developing novel targets for pharmacologic manipulation.